PROJECT SUMMARY This R35 proposal is designed to consolidate two R01 programs, ES005703 and ES020668 into one program with an emphasis on understanding how environment influences human health through the PAS sensor family of proteins. Our approach is to use a highly experienced team, a broad spectrum of biochemical and genetic reagents, a transdisciplinary approach, and the expertise of an array of collaborators and clinician scientists to define the roles that PAS sensors play in environmentally influenced disease states such as cancer, infertility, obesity, diabetes and inflammatory bowel disease. Our overarching idea is that PAS sensors, and their related environmental signals, are impinging on almost every aspect of human health through their capacity as sensors of circadian time, oxygen status, chemical exposure and microbiome changes. We propose that by understanding these pathways, we can not only identify important gene by environment, and environment by environment interactions, but that we can use this information to develop intervention strategies in numerous environmental scenarios likely to be causing human morbidity. Our vision is to understand these pathways through the prism of the Ah receptor (AHR) and through the overarching idea that these pathways are in fact interacting through shared partners, cofactors or ligands. We propose that the insights gained from the R35 will ultimately be useful in intervention strategies to manipulate these pathways via therapeutics or to guide/modify human behavior or the human environment in a manner that is most beneficial to sensitive populations. Over the next eight years, this consolidated R35 should give us the freedom and power to make considerable advances in our understanding of PAS sensors and how they influence human health.